Strong metal-support interactions (SMSIs) are important in heterogeneous catalysis to control stability, activity, and selectivity. Core-shell nanostructures as a unique SMSI system not only stabilize the metal nanoparticles in the core, but also offer tunable structural and electronic properties via their interaction with the support shell. The Au@NiOx core-shell system, for example, is the first commercial nanogold catalyst to produce bulk chemicals via the oxidative esterification of aldehydes. However, how the SMSI effect in Au@NiOx manifests on its oxidative esterification activity is unclear. Here we use a model of an Au13@(NiO)48 core-shell nanocatalyst to examine the Au-NiO interaction and the associated electronic and geometric factors in enabling the oxidation of a hemiacetal (an intermediate from a ready reaction between an aldehyde and an alcohol) to an ester. We found 1.27 (e-) electrons flowing from the NiO shell to the Au core, leading to a higher oxide state of Ni atoms and the stabilization of key intermediates on the NiO shell. More importantly, lower activation energy was found on the Au13@(NiO)48 catalyst than on the Au(111) and NiO(100) surfaces for the rate-limiting step. Microkinetic modeling confirmed the high activity of the Au13@(NiO)48 catalyst in ester production in the experimental temperature range. Our work demonstrates the unique geometric and electronic effects of the Au@NiOx core-shell nanostructure on the catalytic oxidative esterification of aldehydes.